What’s bugging your gut? Let’s focus on the bugs!! Christina Surawicz MD Professor of Medicine Division of Gastroenterology

Topics What does our gut do? What is the microbiome and what does it do? What happens when the microbiome becomes altered? What can we do to keep our gut healthy?

Our luminal GI tract Esophagus Stomach Small intestine Colon (large intestine)

The esophagus Has 2 main jobs: Get food from the mouth to the stomach and To keep it there

The stomach Grinds the food into small particles Pass those small particles gradually into the stomach Minor role in digesting food, producing acid to fight infections

Digestion and Absorption The small intestine Digestion and Absorption Digests food (carbohydrates, proteins, fats) into small compounds that can be absorbed (amino acids, small sugars etc. )with the help of enzymes from the pancreas and bile from the gall bladder Absorbs these nutrients, salt and water chyme

Colon (large intestine) Receives a liter of chyme but puts out 200 grams of stool/day—liquid to solid stool Absorbs salt and water Store until convenient to evacuate Anal sphincter is the smartest sphincter Normal: 3 BM/day to one BM every 3 days Salvages calories from food the small intestine can’t digest like roughage

How does our colon salvage undigested food? Our microbiota does it! What we used to call our gut flora….

What is the microbiota? Microbes= bacteria, fungi, viruses, Microbiome=microbes and their genes In our gut More microbes than any other part of our body, even skin 10 x more cells than all the cells in our body 100 trillion! 1000 species

Our microbiome—Skin and Gut Skin and gut each have 1,000 different bacterial strains Encodes physiologic abilities that our own genome does not We and our Microbiome = A Super-organism! Washington University St Louis Genome sciences Website

Where does our microbiota come from? Our gut is sterile at birth Babies get bugs in: Birth canal, breast milk Environment Food Stable by age 3 Changes again: Puberty Pregnancy Aging

What does Our Microbiota Do? Carbohydrate metabolism Bacteria ferment unabsorbed carbs, produce fatty acids that are fuel for our colon but also gas Vitamin synthesis Important for immune system development More on this later– Dr. Afzali Colonization resistance Protects us from all the germs we ingest from the environment

Bacteroidetes And Firmicutes

What happens when our microbiome gets perturbed? The biggest culprit: ANTIBIOTICS Antibiotics - change the bacteria in the colon and cause diarrhea in 10-20% Usually better when antibiotics are stopped A severe form of antibiotic diarrhea is due to Clostridium difficile A gram positive anaerobic bacteria that infects the colon

Clostridium difficile infection It produces toxins that cause colon disease It forms spores that are very hardy in the environment Most of us don’t get sick because our colon microbiota protects us

Clostridium difficile infection Since the year 2000 there has been a dramatic increase in cases – more severe, more deaths Hypervirulent strain Half a million cases / year in US 29,000 deaths / year in US

CDI cases by age 85 yo 85 + 75-84 yo 75-84

Common Risk Factors Antibiotics –in prior 2 months, especially broad spectrum and multiple antibiotics Recent hospitalization or being in a long term care facility Age over 65 Co-morbid conditions Immunosuppression

Symptoms of C difficile infection Diarrhea Can be mild or very severe Usually watery Crampy abdominal pain Severe cases: colitis, fever, tender abdomen When severe may require surgery to remove the sick colon May be fatal

Severe Clostridium difficile infection Normal colon Pseudomembranes Pseudomembranous colitis

Treatment of C difficile infection Oral Antibiotics: metronidazole or vancomycin or fidaxomicin Severe cases: need IV antibiotics Very severe cases: may need surgery (remove colon or temporary bypass of colon)

Recurrent C difficile infection Most CDI responds to standard therapy 10-20% will have a recurrence After one recurrence, further recurrences are even more likely These are hard to treat: using an antibiotic to treat a disease that is usually the result of an antibiotic Vicious cycle!

Why does this happen?

Treatment of RCDI Repeat antibiotics are needed---with metronidazole or vancomycin, but pulse suggesting that spores germinate on off days, and bugs can normalize on off days Probiotics sometimes work

Russians in Caucasus lived a long time and ate a lot of yogurt What is a probiotic? A substance that stimulates the growth of beneficial bacteria in the alimentary and gastrointestinal tracts and that thus benefits the host as well. Russians in Caucasus lived a long time and ate a lot of yogurt

Saccharomyces boulardii A probiotic nonpathogenic yeast We studied in 1980’s It decreased antibiotic associated diarrhea It treated some patients with recurrent C difficile infection This is actually how I got interested in C diff. But it didn’t work all the time….

Fecal enemas successful – 1 case RCDI Therapy Fecal enemas successful – 1 case Schwan Lancet 1983 Rectal instillate of a mixture of 10 aerobic and anaerobic bacteria – 6 patients Bacteroides restored Tvede and Rask Madsen, Lancet 1989

Patient SW 42 year old woman Retained placenta after birth of first son Prolonged hospitalization plus antibiotics C. difficile – 3 episodes Rx Metronidazole x 2 Final – Vancomycin taper and Saccharomyces boulardii Got better

However, 10 months after 2nd son Diarrhea again Recurs in 1 week, bloody Almost continuously on Vancomycin for 9 months 3 recurrences Vancomycin taper / pulse Saccharomyces boulardii Recurs within 1 week

Time for me to try stool transplant 2004 1990’s – my opinion: desperate patients and desperate doctors 2004 – This case: no other options Husband donor Delivered stool by colonoscopy She was cured and I was convinced

Fecal Microbiota Transplant aka Stool Transplant Healthy donor stool to colon via enema, colonoscopy or upper-tract Rationale: restore normal microbiome

When was stool transplant first documented? 1700 years ago in China? 1958 in post op patients in Denver? On Grey’s Anatomy in 2008?

Answer = A 1700 years ago in China, 4th Century used human feces to treat severe diarrhea; 16th century used infant feces, called “yellow soup” Grey’s Anatomy – 2008 “In the Midnight Hour”, done in emergency room Zhang et al, Am J Gastroenterol 2012; 107:1755 (letter)

Where did this idea come from? In 1958, a surgeon in Denver treated patients who got a severe pseudomembranous colitis after surgery with enemas of stool They got better! We forgot about this strategy until decades later when we started to see more severe C diff infection and nothing else was working. We found out about the Chinese practice a few years ago

90% overall for recurrent CDI Several randomized trial prove it works How well does FMT work? 90% overall for recurrent CDI Several randomized trial prove it works Several routes for getting stool into the colon Enemas Colonoscopy Upper GI route NG tubes or tube into the small bowel

How do I do FMT? Choose the right patient Make sure it is recurrent CDI and that there have been proper prior treatments Explain it is investigational but permitted by the FDA, that we cannot guarantee it will work Find a donor

Usually family, friend or stool bank Donor Selection Usually family, friend or stool bank Extensive initial questionnaire, like for blood donation, including Cancer Autoimmune disorders Metabolic syndrome GI disease or GI symptoms Test blood and stool for pathogens

Obesity related to microbiome and diet– of mice and men/women Microbiota from lean twin to obese mouse: mouse lost weight Microbiota from obese twin to lean mouse: mouse gained weight (Jeffrey Gordon’s work; Science Sept 6, 2013) Identical twins

Did fecal transplant make woman obese? 32 y.o. woman gained 40 lbs. and rising after FMT for RCDI Her BMI: 26 to 33 (thin to start) Not able to lose the weight Donor: 16 yo daughter was obese Was the new colon bacteria responsible??? Alang and Kelly, Open forum infectious diseases November 2014

A lot of interest FMT Remarkable efficacy for recurrent C difficile infection (90%) A “natural” approach, simple Special interest in inflammatory bowel disease No immune suppression Both C diff and IBD have dysbiosis so it might work---research being done in patients PLEASE DON’T TRY THIS AT HOME

The media/lay press is full of stories of lives saved by FMT (often self-administered). There are guidebooks for patients and Online resources such as the fecal transplant foundation, “the power of poop,” and Youtube videos describe DIY FMT.

Some short term complications Long term effects? We do not know Some short term complications Fever, infection rare, constipation, bloating May have long term effects We need studies to know if FMT will be effective in other diseases

Wise antibiotic policies How do we prevent CDI? Wise antibiotic policies Clindamycin, Cephalosporins, Quinolones are highest risk Hand hygiene (soap and water), barrier and isolation in the hospital Probiotics not ready for prime time in my opinion

How can we keep our gut healthy? Regular meals; gut likes predictability Avoid unnecessary medications, especially antibiotics Exercise is good, improves transit Healthy people don’t need probiotics But fermented foods may be good Kimchee, yogurt and kefir, sauerkraut

Healthy foods More fruits and vegetables Whole grains Nonfat or low fat dairy Seafood Nuts Legumes (beans, peas, lentils, etc.)

Avoid or limit Refined grains Processed meat Sugary sweet drinks White bread Processed meat Hot dogs, ham, sausage, bacon Sugary sweet drinks Soda Red meat---3/week max Chemicals---can’t pronounce it? Don’t eat it.

Summary What our gut does What our microbiome does C difficile infection Keeping our gut healthy